Females with dystrophinopathy

Why women can have Duchenne

Why can women have Duchenne? The dystrophin gene is located on the X-chromosomes. Men have only one X chromosomes, so if the gene is mutated, they do not have a back up copy and cannot produce dystrophin and have Duchenne. Women have two X-chromosomes, so if one is mutated, they have a back up copy that can make dystrophin. This is why they generally do not have Duchenne.

There are exceptions however why women can also have Duchenne. The scientific term for women with Duchenne is called females with dystrophinopathy. There are three cases where a women can have Duchenne: by having a Duchenne father and a carrier mother, by skewed X-inactivation, and by chromosomal mixup.

1. Father with Duchenne, carrier mother

The first case is when a woman has two X-chromosomes with mutated dystrophin genes. This is very rare, as this would require the father to have Duchenne and the mother to be a carrier.

2. Skewed X-inactivation

The second case is skewed X-inactivation. Some advanced genetics: women have 2 X-chromosomes, but only one of the 2 is active in each cell. When an embryo is about 200 cells, each cell decides to inactivate the X-chromosome it got from the father or to inactivate the X-chromosome it got from the mother. After this decision, the pattern will be inherited by each of the daughter cells. Generally roughly 50% of cells will inactivate the maternal X-chromosome and 50% of the cells will inactivate the paternal X-chromosome.

When one of the X-chromosomes contains a mutated dystrophin gene, cells in which this X-chromosome is active will not be able to produce dystrophin. So carriers have 50% of muscle fibers that produce dystrophin and 50% of fibers that do not produce dystrophin. In most women that is enough to prevent pathology, but some will experience symptoms due to this. It is also possible that the X-inactivation is not random but skewed in favor of one of the 2 X-chromosomes. This can result in e.g. 70% of the fibers being able to produce dystrophin (good) or only 30% (or even less) of the fibers being able to produce dystrophin (not so good).

3. Chromosomal mixup

The final case is when a woman has a large chromosomal mixup (translocation). Here part of one chromosome is swapped with part of another chromosome. If this involves the X-chromosome and the break is through the dystrophin gene, the gene is no longer working.

The woman will have a spare X-chromosome, with a functional dystrophin gene, but she won’t be able to use this: during X-inactivation in the embryo, only the cells in which the mutated X-chromosome is active will survive. This is because in the other cells the X-chromosome will also carry part of another chromosome and inactivating that is incompatible with life. As such, for these women the X-chromosome with the functional dystrophin gene is inactivated in each of the muscle fibers. Thus they cannot produce any dystrophin and have full blown Duchenne.